Antithrombotic properties of RWJ-50353, a potent and novel thrombin inhibitor

The antithrombotic, anticoagulant, and kinetic properties of RWJ-50353, a n ovel, reversible, active-site-directed thrombin inhibitor, were evaluated. RWJ-50353 inhibited the catalytic activity of human alpha-thrombin with a K -i of 0.19+/-0.02 nM. It showed a 16-fold selectivity relative to inhibitio n of trypsin and at least 330-fold selectivity relative to inhibition of ot her biologically important serine proteases. In a gel-filtered platelet pre paration, RWJ-50353 inhibited alpha-thrombin-induced aggregation with an IC 50 of 32+/-6 nM. In a canine arteriovenous shunt antithrombotic model, RWJ- 50353 demonstrated a significant dose-related (0.1-1.0 mg/kg, i.v.) reducti on in thrombus formation with 50% inhibition (ID50) obtained at 0.46+/-0.1 mg/kg. In a rabbit deep vein thrombosis model, RWJ-50353 dose-dependently ( 0.1-1.0 mg/kg, i.v.) reduced thrombus formation with an ID50 of 0.25+/-0.03 mg/kg. The antithrombotic activity in both of these models was associated with only mild prolongations in bleeding time and coagulation parameters. T hese results demonstrate that RWJ-50353 is a potent, selective thrombin inh ibitor that is an effective antithrombotic agent after intravenous administ ration in models of arterial and venous thrombosis and may be useful in the management of various thrombotic disorders. (C) 2000 Elsevier Science Ltd. All rights reserved.